TEMPO-Mediated Synthesis of N-(Fluoroalkyl)imidazolones via Reaction of Imidazoles with Iodofluoroacetate

Article abstract of DOI:10.1002/adsc.201900820

We report a TEMPO-mediated oxidative copper-catalyzed synthesis of N-(fluoroalkyl)imidazolones via the radical addition of imidazoles with iodofluoroacetate. A possible key intermediate involving TEMPO was observed by ESI-MS. We also found that aerobic ox

Full text of DOI:10.1002/adsc.201900820

Title: TEMPO-Mediated Synthesis of N-(Fluoroalkyl)imidazolones via
the Reaction of Imidazoles with Iodofluoroacetate
Authors: Jia-Hao Chen, Ahmed Wasim, Ming-Hua Li, Zhao-Dong Li, Zi-
Ning Cui, and Ri-Yuan Tang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900820
Link to VoR: http://dx.doi.org/10.1002/adsc.201900820

10.1002/adsc.201900820
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
TEMPO-Mediated Synthesis of N-(Fluoroalkyl)imidazolones
via Reaction of Imidazoles with Iodofluoroacetate
Jia-Hao Chen,a Ahmed Wasim,a Ming-Hua Li,a Zhao-Dong Li,a Zi-Ning Cui*ac and Ri-
Yuan Tang*ab
a
Department of Applied Chemistry, College of Materials and Energy, State Key Laboratory for Conservation and
Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou 510642, P. R. of China
[rytang@scau.edu.cn, ziningcui@scau.edu.cn]
Key Laboratory of Natural Pesticide & Chemical Biology, Ministry of Education, South China Agricultural University,
b
Guangzhou 510642, P. R. of China
Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease
c
Control, South China Agricultural University, Guangzhou 510642, P. R. of China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
developed an efficient and practical sulfite-promoted
Abstract. We report a TEMPO-mediated oxidative
copper-catalyzed synthesis of N-(fluoroalkyl)imidazolones synthesis
of
N-(fluoroalkyl)
or
through
N-
the
via the radical addition of imidazoles with
iodofluoroacetate. A possible key intermediate involving
TEMPO was observed by ESI-MS. We also found that
aerobic oxidation conditions were effective for the
transformation in the presence of a copper catalyst,
(difluoromethyl)imidazothiones
fluoroalkylation and sulfurization of imidazoles with
elemental sulfur and ethyl 2-bromo-2-fluoroacetate (or
ethyl 2-bromo-2,2-difluoroacetate).[13] This work
aimed at incorporating a fluoroalkyl group into
heterocycles for use as novel medicines and
agrochemicals.[14] We therefore attempted to
synthesize N-(fluoroalkyl)imidazolones for the
development of pesticides. However, we found that the
sulfite-promoted methods were not suitable for the
synthesis of N-(fluoroalkyl)imidazolones. The
development of new synthetic strategies for such
transformations is needed. Herein, we report a
TEMPO-mediated oxidative synthesis of N-
(fluoroalkyl)imidazolones by the radical addition of
imidazoles with fluoroalkyl radicals generated from
iodofluoroacetate (Scheme 1b).
enabling
access
to
a
number
of
N-
(fluoroalkyl)imidazolones in moderate to good yields.
Keywords: Imidazolone; Copper; TEMPO; Aerobic
oxidation; Radical reaction
Introduction
Imidazolones are found frequently in medicines.[1-5]
Several natural products possess 2-imidazolones as
their core structure.[1] Such skeletons are common in
pharmaceutically interesting compounds such as
human dopamine D4 receptor antagonists,[2] MurB
enzyme inhibitors,[3] potential antitumor agents,[4] and
antioxidants.[5] Due to the medicinal importance of
imidazolones, much effort has been devoted to their
synthesis.[6-12] In recent years, the oxidation of
imidazolium salts using strong oxidants has proven to
be an effective pathway to imidazolones (Scheme
1a).[6-9] Ollevier and colleagues recently demonstrated
Scheme 1. Synthetic methods for the preparation of N-
(fluoroalkyl)imidazolones.
that
imidazolidinone,
imidazolone,
and
benzimidazolone derivatives could be synthesized
efficiently via the oxidation of imidazolium salts using
a copper catalyst and air as an oxidant at room
temperature.[9b] However, this route requires the initial
synthesis of imidazolium salts. In 2013, Guo and
coworkers developed a copper/DTBP (Di-tert-butyl
peroxide)-catalyzed oxidation of imidazolium salts,
formed in situ via the nucleophilic substitution of alkyl
halides with imidazoles.[10] Very recently, we
1
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10.1002/adsc.201900820
Advanced Synthesis & Catalysis
Table 1. Screening of optimal conditions [a]
.
Results and Discussion
Our study began with the reaction of 1-methyl-
benzimidazole 1a with ethyl 2-fluoro-2-iodoacetate 2a
in the presence of CuBr2 and TEMPO in different
solvents (Table 1, Entries 1-6). Solvents such as
toluene, dioxane, CH3CN, and DMF are effective for
this reaction and offer the target product 3 in moderate
yields (Table 1, Entries 1-4). However, the reaction did
not proceed in DMSO (Table 1, Entry 5). An excellent
yield (96%) was obtained when the reaction was
conducted in DCE (Table 1, Entry 6). Carrying out the
reaction at 60 °C furnished the product in lower yield
(69%), a result of the low conversion of compound 1a
(Table 1, entry 7). Reaction at 100 °C produced some
unknown byproducts, leading to a decrease in yield
(67%) (Table 1, Entry 8). To further investigate the
effect of copper catalysts, CuCl2, Cu(OAc)2, CuO, and
CuBr were examined with good yields (82%-87%,
Table 1, Entries 9–12). Interestingly, carrying out the
reaction with TEMPO still furnished the target product
in 62% yield in the absence of copper catalyst (Table
1, Entry 13). Further studies showed that the reaction
still proceeded smoothly under an N2 atmosphere and
the desired product was afforded in a similar yield to
that obtained when the reaction was carried out in air
(Table 1, Entry 14 vs Entry 6, Entry 15 vs Entry 13).
These results indicate that TEMPO plays a key role in
the transformation. To compare these results with the
effect of traditional oxidants, K2S2O8, Oxone and
TBHP were employed in the reaction, but use of these
oxidants resulted in much lower yields of the desired
product (12%, 8%, and 54%, respectively; Table 1,
Entries 16-18). Air can be used as a green oxidant,[15]
and so the reaction was conducted in the presence of
CuBr2 and air to provide the target product 3 in 36%
yield (Table 1, Entry 19). The yield was greatly
increased to 83% under an O2 atmosphere (Table 1,
Entry 20). A gram-scale reaction proved the good
scalability of this reaction; product 3 was obtained in
81% yield with 8 mmol of compound 1a (Table 1,
entry 6).
The reaction scope was studied with these optimized
conditions in hand. In the presence of CuBr2 and
TEMPO, a variety of significant functional groups
such as chloro, bromo, fluoro, methoxy, ester, and
nitro substituents were well tolerated and furnished
their corresponding products 3-12 in moderate to good
yields (Table 2). We note that a range of modifications
can be made on these functional groups. Starting
materials bearing an electron-withdrawing group were
not completely converted, leading to moderate yields
(products 6-12). The scope of different N-substituents
on the benzimidazoles was also investigated (products
13-22). Numerous functional groups, such as ether,
nitrile, alkene and aryl functionalities were also
amenable to the reaction conditions and afforded their
corresponding products 13-22 in yields of 58% to 93%.
Imidazopyridine also furnished its corresponding
product 23 in 56% yield. Importantly, N-aryl-
substituted imidazoles were also compatible with the
Entry
[Cu]
Oxidant
Solvent
Yield (%)
1
2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuCl2
Cu(OAc)2
CuO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
K2S2O8
Oxone
Toluene
Dioxane
CH3CN
DMF
DMSO
DCE
75
67
3
69
4
47
5
0
6
96 (81)e
7 [b]
8 [c]
9
DCE
69
DCE
67
DCE
87
10
11
12
13
14 [d]
15 [d]
16
17
18
19
20
DCE
82
DCE
82
CuBr
DCE
83
―
DCE
62
CuBr2
―
DCE
95
DCE
64
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
DCE
12
DCE
8
TBHP
DCE
54
Air
DCE
36
O2
DCE
83
[a]
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol, 2
equiv.), [Cu] (10 mol%), oxidant (0.4 mmol, 2 equiv.),
solvent (2 mL), at 80 C, reaction for 24 h. [b] at 60 C. [c] at
100 C. [d] under N2. [e] gram-scale reaction: 1a (8 mmol), 2a
(16 mmol, 2 equiv.), [Cu] (10 mol%), TEMPO (16 mmol, 2
equiv.), DCE (50 mL), at 80 C, reaction for 24 h.
optimized reaction condition to yield products 24 and 25 in
68% and 41% yields, respectively. Such compounds are
structurally related to a number of herbicides.[16]
Generally, imidazoles are less reactive than
benzimidazoles, hence the conjugation effect between
the benzene ring and imidazole ring may facilitate
transformation. The reaction still proceeded for
substrates lacking a fluoro group but with the
corresponding products being obtained in lower yields.
For example, reaction of 2a provided the
corresponding products 26-29 in yields of 31-68%.
This indicates that the fluoro group in 2a can enhance
the reactivity via formation of an alkyl free radical.
The low yields mostly result from the decomposition
of iodoalkanes and the formation of unknown
byproducts. ICF2CO2Et was also subjected to the
reaction conditions, but the corresponding product was
not obtained. Neither benzothiazole nor benzoxazole
were suitable for this reaction. Since a good yield was
obtained under aerobic conditions (Table 1, Entry 20),
these reactions were also conducted in the presence of
2
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10.1002/adsc.201900820
Advanced Synthesis & Catalysis
CuBr2 and O2 (Table 2); the desired products were
obtained in moderate to good yields. Generally, O2 is
less effective than TEMPO in such transformations.
For products 6 and 7, using O2 proved more efficient
than TEMPO. However, CuBr2/O2 is not suitable for
the formation of product 24.
TEMPO in the absence of copper catalyst, none of the
target product 26 was observed (Scheme 2, eq. 2 vs
Table 1, entry 13). These results suggest that this
reaction pathway differs from previous methods
involving an imidazolium salt.[6-9] The N-methyl
benzimidazole 1a did not furnish the required
benzimidazolone in the absence of alkyl halide under
standard conditions (Scheme 2, eq. 3). ESI-MS real-
time analysis showed the presence of compounds 31
and 32 in the reaction mixture (Scheme 2, eq. 4; see
the SI). Further studies showed that compound 31 can
be quantitatively prepared from the reaction of
TEMPO with iodofluoroacetate at 120 °C without any
additives (see the SI); however, its reaction with 1a
did not afford the target product 3 (Scheme 2, eq. 5).
Intermediate 32 disappears as the reaction progresses.
These results clearly indicate that compound 31 is not
an intermediate but a byproduct, and that compound
32 is a reaction intermediate. In the presence of the
radical trapping reagent BHT (2,6-di-tert-butyl-4-
methylphenol), the reaction was completely suppressed,
and no target product was observed suggesting that the
reaction may undergo a free radical process (Scheme
2, eq. 5).
Table 2. Reaction scope of imidazoles [a]
.
Scheme 2. Control experiments.
[a]
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol, 2
equiv.), CuBr2 (10 mol%), TEMPO (0.4 mmol, 2 equiv.),
[b]
solvent (2 mL), at 80 C, reaction for 24 h. reaction for
36 h. Reaction conditions for the yield of parentheses:
TEMPO was replaced with O2 (1 atm).
Based on the results of the control experiments and
previous work,[13,15] a plausible reaction mechanism is
depicted in scheme 3. CuBr2 may act as a redox agent
for the oxidation of 1a to species A. The resulting
Cu(I) species could be reoxidized to Cu(II) via
Next, we focused on understanding the mechanism of
this TEMPO mediated reaction. Several control
experiments were conducted to understand the role of
TEMPO (Scheme 2). No benzimidazolium species
was detected by ESI-MS analysis via the reaction of
1a with 2a in the absence of TEMPO (Scheme 2, eq.
1). When the benzimidazolium salt 30 was treated with
conversion
of
TEMPO
to
2,2,6,6-
tetramethylpiperidin-1-olate B. Under heating
conditions, iodofluoroacetate 2a may undergo
mesolytic cleavage of the C-I bond to afford a radical
3
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10.1002/adsc.201900820
Advanced Synthesis & Catalysis
C,[17] which then undergoes radical addition with 1a
and TEMPO to form intermediate 32.[18] Radical C
may couple with intermediate A to produce
intermediate D, which upon addition with intermediate
B gives 32. Finally, intermediate 32 undergoes a β-
elimination to afford 2,2,6,6-tetramethylpiperidine
and target product 3.
spectrometer. LC-MS (ESI) analysis was measured on an
AB Sciex API3200. IR spectra was measured on a Nicolet
IS10. HRMS (ESI) analysis was measured on a Thermo
Scientific LTQ Orbitrap XL.
General procedure for the synthesis of N-
(Fluoroalkyl)imidazolones 3-29: A 15 mL sealed tube
(with a Teflon cap) equipped with a magnetic stir bar was
charged with imidazole (0.20 mmol), CuBr2 (10 mol%) and
TEMPO (0.40 mmol, 2 equiv). DCE (1.0 mL) was added to
the mixture, followed by alkyl halide (0.4 mmol, 2 equiv)
and, finally, another portion of DCE (1.0 mL). The tube was
then capped and submerged into an oil bath pre-heated to 80
C. The reaction was stirred for 24 h or 36 h and cooled to
room temperature. An excess of anhydrous Na2S2O3 was
added to the reaction mixture, diluted with ethyl acetate (5
mL) and filtered through a short pad of celite washing with
an additional 20 mL ethyl acetate. The filtrate was
concentrated in vacuo, and the resulting residue was purified
by flash column chromatography using n-hexane or
petroleum ether and ethyl acetate as the eluent.
Scheme 3. A plausible reaction pathway.
Experimental procedure for the preparation of
compound 30: A 50 mL round bottom flask, equipped with
a magnetic stirrer bar was charged with 1-methyl-
benzimidazole (4.0 mmol), ethyl iodoacetate (1.2 equiv.)
and ethyl acetate (20 mL). The reaction mixture was stirred
at room temperature overnight. After the completion of the
reaction, ethyl acetate was removed in vacuo, and the
residue was washed with diethyl ether. The
benzimidazolium salt 30 was obtained as a white solid.
Experimental procedure for the in situ preparation of
compound 31: A 15 mL sealed tube (with a Teflon cap)
equipped with a magnetic stirrer bar was charged with
TEMPO (0.40 mmol, 2 equiv), DCE (1.0 mL), 2-fluoro-2-
iodoacetate 2a (0.4 mmol, 2 equiv) and, finally, another
portion of DCE (1.0 mL). The tube was then capped and
submerged into an oil bath pre-heated to 120 C. The
reaction was stirred for 12 h and then cooled to room
temperature. The reaction mixture was directly used for
control experiments (see Scheme 2, eq. 5).
Ethyl
2-fluoro-2-(3-methyl-2-oxo-2,3-dihydro-1H-
Conclusion
benzo[d]imidazol-1-yl)acetate
(3).
CAS
number:
1516303-22-2. Yellow solid. M.P.: 83.1 – 84.6 C. 96%
1
In summary, we have developed a novel and
convenient strategy for the transformation of
imidazoles into N-(fluoroalkyl)imidazolones via a
radical addition of imidazoles with iodofluoroacetate
and TEMPO. This new chemistry facilitates the
formation of a number of products in moderate to
excellent yields. It is worth noting that N-(fluoroalkyl)
imidazolones could also be synthesized under aerobic
oxidation conditions. Good functional group tolerance
allows for the preparation of a number of diverse
products which are of great interest in drug and
pesticide development.
Yield (48 mg, Eluent: EtOAc/petroleum = 1:5). H NMR
(600 MHz, CDCl3) δ 7.16 – 7.13 (m, 1H), 7.07 (q, J = 7.8
Hz, 2H), 6.98 (d, J = 7.8 Hz, 1H), 6.65 (d, J = 48.0 Hz, 1H),
4.36 – 4.24 (m, 2H), 3.39 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H).
13C NMR (151 MHz, CDCl3) δ 164.65 (d, JC-F = 35.9 Hz,
1C), 153.11, 130.21, 126.16 (d, JC-F = 2.9 Hz, 1C), 123.12,
122.07, 109.32, 108.12, 85.05 (d, JC-F = 212.2 Hz, 1C),
62.99, 27.30, 13.97. IR (KBr, cm-1): 2924, 2853, 1765, 1724,
1620, 1497, 1434, 1393, 1373, 1056, 1023, 753.
Ethyl
2-fluoro-2-(6-methoxy-3-methyl-2-oxo-2,3-
dihydro-1H-benzo[d]imidazol-1-yl)acetate (4). Yellow
solid. M.P.: 103.3 – 104.1 C. 91% Yield (51 mg, Eluent:
1
EtOAc/petroleum = 1:4). H NMR (600 MHz, CDCl3) δ
6.87 (d, J = 8.3 Hz, 1H), 6.75 – 6.68 (m, 2H), 6.63 (d, J =
47.9 Hz, 1H), 4.38 – 4.25 (m, 2H), 3.77 (s, 3H), 3.37 (s, 3H),
1.25 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ
164.63 (d, JC-F = 36.1 Hz, 1C), 155.88, 153.28, 126.92 (d,
JC-F = 3.0 Hz, 1C), 124.15, 108.55, 108.43, 96.74, 85.06 (d,
JC-F = 212.2 Hz, 1C), 62.98, 55.94, 27.32, 14.00. IR (KBr,
cm-1): 2952, 2907, 2835, 1764, 1721, 1631, 1613, 1503,
1430, 1396, 1289, 1211, 1160, 1050, 1023, 745, 692. HRMS
Experimental Section
General Methods
(ESI) for C13H16FN2O4 (M+H)+: calcd 283.10886, found
+
1H and 13C NMR spectra were measured on a Bruker
1
283.10907.
Avance-Ⅲ600 instrument (600MHz for H, 151 MHz for
13C NMR spectroscopy) using CDCl3 as the solvent.
Chemical shifts for H and 13C NMR were referred to
1
Ethyl
2-(6-bromo-3-methyl-2-oxo-2,3-dihydro-1H-
internal Me4Si (0 ppm) as the standard. The following
abbreviations (or combinations thereof) were used to
explain chemical shift (δ ppm), multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet), integration,
and coupling constants (J) in hertz (Hz). GC-MS (EI)
analysis was measured on an Agilent GC-MS-5975C Plus
benzo[d]imidazol-1-yl)-2-fluoroacetate (5). Yellow solid.
M.P.: 124.3 – 125.4 C. 88% Yield (58 mg, Eluent:
1
EtOAc/petroleum = 1:4). H NMR (600 MHz, CDCl3) δ
7.28 (d, J = 8.3 Hz, 1H), 7.24 (s, 1H), 6.86 (d, J = 8.3 Hz,
1H), 6.61 (d, J = 47.6 Hz, 1H), 4.42 – 4.26 (m, 2H), 3.39 (s,
3H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3)
4
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10.1002/adsc.201900820
Advanced Synthesis & Catalysis
δ 164.22 (d, JC-F = 35.5 Hz, 1C), 152.78, 129.36, 127.22 (d,
JC-F = 2.9 Hz, 1C), 125.99, 114.60, 112.73, 109.26, 85.06 (d,
JC-F = 213.6 Hz, 1C), 63.20, 27.42, 13.98. IR (KBr, cm-1):
2956, 2924, 2852, 1730, 1619, 1604, 1494, 1429, 1391,
δ 165.83, 165.15 (d, JC-F = 30.5 Hz, 1C), 153.44, 132.03,
127.09 (d, JC-F = 3.1 Hz, 1C), 124.62, 122.35, 115.68,
111.88, 87.19 (d, JC-F = 217.1 Hz, 1C), 62.57, 61.87, 27.38,
14.13, 14.01. IR (KBr, cm-1): 2956, 2924, 2853, 1770, 1736,
1650, 1615, 1468, 1392, 1371, 1260, 1223, 1053, 1018, 756.
1223, 1047, 1016, 799, 747, 696. HRMS (ESI) for
+
+
C12H13BrFN2O3
331.00928.
(M+H)+: calcd 331.00881, found
HRMS (ESI) for C15H18FN2O5 (M+H)+: calcd 325.11943,
found 325.11969.
Ethyl
2-(6-chloro-3-methyl-2-oxo-2,3-dihydro-1H-
Ethyl 2-fluoro-2-(3-methyl-6-nitro-2-oxo-2,3-dihydro-
1H-benzo[d]imidazol-1-yl)acetate (11). Yellow solid.
M.P.: 105.3 – 106.3 C. 44% Yield (26 mg, Eluent:
benzo[d]imidazol-1-yl)-2-fluoroacetate (6). Light yellow
solid. M.P.: 93.0 – 93.7 C. 74% Yield (42 mg, Eluent:
1
1
EtOAc/petroleum = 1:4). H NMR (600 MHz, CDCl3) δ
EtOAc/petroleum = 1:3). H NMR (600 MHz, CDCl3) δ
7.06 (dd, J = 8.4, 1.8 Hz, 1H), 7.04 – 6.99 (m, 2H), 6.63 (d,
J = 47.6 Hz, 1H), 4.38 – 4.25 (m, 2H), 3.41 (s, 3H), 1.26 (t,
J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 164.36 (d,
JC-F = 35.8 Hz, 1C), 153.06, 131.23, 128.88, 124.72 (d, JC-F
8.09 (dd, J = 8.7, 2.2 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.21
(d, J = 8.7 Hz, 1H), 6.68 (d, J = 46.9 Hz, 1H), 4.41 – 4.29
(m, 2H), 3.52 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR
(151 MHz, CDCl3) δ 163.90 (d, JC-F = 34.9 Hz, 1C), 153.08,
144.08, 131.04 (d, JC-F = 2.7 Hz, 1C), 130.58, 118.78,
109.19, 103.93, 85.03 (d, JC-F = 214.5 Hz, 1C), 63.47, 27.81,
14.00. IR (KBr, cm-1): 2954, 2924, 2853, 1736, 1618, 1523,
1500, 1430, 1392, 1337, 1225, 1041, 1015, 752. HRMS
= 2.9 Hz, 1C), 121.98, 110.28, 108.67, 85.04 (d, JC-F
=
212.89 Hz, 1C), 63.13, 27.48, 13.99. IR (KBr, cm-1): 3079,
2982, 2930, 2855, 1732, 1623, 1607, 1499, 1430, 1392,
1373, 1226, 1048, 1017, 802, 750. HRMS (ESI) for
+
+
C12H13FClN2O3
287.05984.
(M+H)+: calcd 287.05932, found
(ESI) for C12H13FN3O5 (M+H)+: calcd 298.08338, found
298.08365.
Ethyl
2-(5-chloro-3-methyl-2-oxo-2,3-dihydro-1H-
Ethyl 2-fluoro-2-(3-methyl-5-nitro-2-oxo-2,3-dihydro-
1H-benzo[d]imidazol-1-yl)acetate (12). Yellow solid.
M.P.: 125.9 – 127.0 C. 39% Yield (23 mg, Eluent:
benzo[d]imidazol-1-yl)-2-fluoroacetate (7). Light yellow
solid. M.P.: 90.5 – 91.5 C. 67% Yield (38 mg, Eluent:
1
1
EtOAc/petroleum = 1:4). H NMR (600 MHz, CDCl3) δ
EtOAc/petroleum = 1:3). H NMR (600 MHz, CDCl3) δ
7.15 (dd, J = 8.3, 1.9 Hz, 1H), 7.12 (d, J = 1.8 Hz, 1H), 6.91
(d, J = 8.3 Hz, 1H), 6.62 (d, J = 47.5 Hz, 1H), 4.42 – 4.29
(m, 2H), 3.41 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR
(151 MHz, CDCl3) δ 164.26 (d, JC-F = 35.5 Hz, 1C), 152.95,
128.89, 127.70, 126.90 (d, JC-F = 2.9 Hz, 1C), 123.16,
110.10, 108.78, 85.04 (d, JC-F = 213.5 Hz, 1C), 63.21, 27.46,
13.99. IR (KBr, cm-1): 3078, 2981, 2925, 2852, 1732, 1622,
8.20 (dd, J = 8.7, 2.0 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.09
(d, J = 8.7 Hz, 1H), 6.67 (d, J = 47.3 Hz, 1H), 4.48 – 4.32
(m, 2H), 3.51 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR
(151 MHz, CDCl3) δ 163.84 (d, JC-F = 34.2 Hz, 1C), 153.21,
143.11, 135.23, 126.10 (d, JC-F = 2.8 Hz, 1C), 120.10,
107.46, 105.64, 85.15 (d, JC-F = 216.0 Hz, 1C), 63.58, 27.84,
14.01. IR (KBr, cm-1): 2955, 2924, 2853, 1742, 1623, 1523,
1607, 1497, 1431, 1394, 1224, 1051, 1018, 801, 749, 703.
1504, 1434, 1393, 1338, 1285, 1044, 1018, 750. HRMS
+
+
HRMS (ESI) for C12H13FClN2O3 (M+H)+: calcd 287.05932, (ESI) for C12H13FN3O5 (M+H)+: calcd 298.08338, found
found 287.05984.
298.08365.
Ethyl 2-(5,6-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-
benzo[d]imidazol-1-yl)-2-fluoroacetate (8). Light yellow
solid. M.P.: 84.2 – 84.8 C. 71% Yield (41 mg, Eluent:
Ethyl
2-(3-butyl-2-oxo-2,3-dihydro-1H-
benzo[d]imidazol-1-yl)-2-fluoroacetate (13). Yellow oil.
1
92% Yield (54 mg, Eluent: EtOAc/petroleum = 1:6). H
1
EtOAc/petroleum = 1:3). H NMR (600 MHz, CDCl3) δ
NMR (600 MHz, CDCl3) δ 7.15 (td, J = 7.7, 1.3 Hz, 1H),
7.11 – 7.06 (m, 2H), 7.02 (d, J = 7.8 Hz, 1H), 6.65 (d, J =
47.9 Hz, 1H), 4.38 – 4.26 (m, 2H), 3.88 (td, J = 7.1, 2.0 Hz,
2H), 1.77 – 1.72 (m, 2H), 1.43 – 1.37 (m, 2H), 1.25 (t, J =
7.1 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz,
CDCl3) δ 164.67 (d, JC-F = 36.0 Hz, 1C), 152.97, 129.72,
126.34 (d, JC-F = 3.0 Hz, 1C), 122.98, 121.84, 109.47,
108.31, 85.13 (d, JC-F = 212.2 Hz, 1C), 62.93, 41.24, 30.15,
20.01, 13.96, 13.64. IR (KBr, cm-1): 3066, 2959, 2929, 2873,
1766, 1723, 1612, 1492, 1398, 1373, 1223, 1171, 1049, 754.
7.05 – 6.98 (m, 1H), 6.89 – 6.82 (m, 1H), 6.62 (d, J = 47.2
Hz, 1H), 4.40 – 4.28 (m, 2H), 3.40 (s, 3H), 1.29 (t, J = 7.2
Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 164.18 (d, JC-F
=
35.7 Hz, 1C), 153.31, 147.72 (dd, JC-F = 243.5, 14.0 Hz, 1C),
146.11 (dd, JC-F = 242.7, 14.1 Hz, 1C), 126.04 (d, JC-F = 10.2
Hz, 1C), 121.37 (d, JC-F = 10.2 Hz, 1C), 100.00 (d, JC-F
24.8 Hz, 1C), 98.01 (d, JC-F = 23.9 Hz, 1C), 85.13 (d, JC-F
=
=
213.4 Hz, 1C), 63.25, 27.60, 13.98. IR (KBr, cm-1): 3065,
2984, 2926, 2854, 1736, 1634, 1510, 1449, 1395, 1223,
1165, 1053, 1019, 851, 790, 747. HRMS (ESI) for
HRMS (ESI) for C15H20FN2O3 (M+H)+: calcd 295.14525,
+
C12H12F3N2O3+ (M+H)+: calcd 289.07945, found 289.07977. found 295.14545.
Methyl
3-(2-ethoxy-1-fluoro-2-oxoethyl)-1-methyl-2-
Ethyl 2-(3-(2-(2-ethoxyethoxy)ethyl)-2-oxo-2,3-dihydro-
1H-benzo[d]imidazol-1-yl)-2-fluoroacetate (14). Yellow
oil. 85% Yield (60 mg, Eluent: EtOAc/petroleum = 1:3). 1H
NMR (600 MHz, CDCl3) δ 7.20 (d, J = 7.8 Hz, 1H), 7.14 (t,
J = 7.3 Hz, 1H), 7.10 – 7.05 (m, 2H), 6.65 (d, J = 48.0 Hz,
1H), 4.39 – 4.25 (m, 2H), 4.13 – 4.03 (m, 2H), 3.84 – 3.75
(m, 2H), 3.59 (t, J = 3.9 Hz, 2H), 3.50 (t, J = 3.6 Hz, 2H),
3.45 (q, J = 7.0 Hz, 2H), 1.26 (t, J = 7.3 Hz, 3H), 1.15 (t, J
= 7.0 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 164.66 (d, JC-
F = 35.8 Hz, 1C), 153.05, 130.15, 126.18 (d, JC-F = 2.8 Hz,
1C), 123.00, 121.95, 109.42, 109.25, 85.07 (d, JC-F = 212.5
Hz, 1C), 70.73, 69.78, 69.01, 66.63, 62.97, 41.68, 15.09,
13.98. IR (KBr, cm-1): 3065, 2971, 2960, 2924, 2856, 1765,
1722, 1618, 1492, 1397, 1375, 1220, 1110, 1059, 1024, 754.
oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate
(9). White solid. M.P.: 118.5 – 119.4 C. 77% Yield (48 mg,
1
Eluent: EtOAc/petroleum = 1:4). H NMR (600 MHz,
CDCl3) δ 7.94 (dd, J = 8.3, 1.3 Hz, 1H), 7.77 (d, J = 1.2 Hz,
1H), 7.03 (d, J = 8.3 Hz, 1H), 6.65 (d, J = 47.9 Hz, 1H), 4.44
– 4.28 (m, 2H), 3.90 (s, 3H), 3.45 (s, 3H), 1.30 (t, J = 7.1
Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 166.47, 164.25 (d,
JC-F = 34.7 Hz, 1C), 153.26, 133.94, 126.02 (d, JC-F = 2.8
Hz, 1C), 125.70, 124.28, 110.52, 107.57, 85.08 (d, JC-F
=
214.6 Hz, 1C), 63.23, 52.19, 27.56, 13.96. IR (KBr, cm-1):
3076, 2954, 2851, 1739, 1716, 1625, 1508, 1468, 1434,
1394, 1377, 1270, 1246, 1103, 1050, 1019, 764. HRMS
(ESI) for C14H16FN2O5 (M+H)+: calcd 311.10378, found
+
+
311.10394.
HRMS (ESI) for C17H24FN2O5 (M+H)+: calcd 355.16638,
found 355.16678.
Ethyl 3-(2-ethoxy-1-fluoro-2-oxoethyl)-1-methyl-2-oxo-
2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (10).
Light yellow solid. M.P.: 111.2 – 112.0 C. 58% Yield (38
Ethyl
2-fluoro-2-(2-oxo-3-((tetrahydrofuran-2-
yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-
1
mg, Eluent: EtOAc/petroleum = 1:3). H NMR (600 MHz,
yl)acetate (15). Yellow solid. M.P.: 71.4 – 72.5 C. 87%
1
CDCl3) δ 7.71 (dd, J = 8.0, 1.1 Hz, 1H), 7.42 (d, J = 48.4
Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.16 (dd, J = 7.8, 1.1 Hz,
1H), 4.41 – 4.35 (m, 4H), 3.42 (s, 3H), 1.40 (t, J = 7.1 Hz,
3H), 1.34 (t, J = 7.2 Hz, 3H). 13C NMR (151 MHz, CDCl3)
Yield (56 mg, Eluent: EtOAc/petroleum = 1:4). H NMR
(600 MHz, CDCl3) δ 7.21 (dd, J = 7.8, 3.2 Hz, 1H), 7.16 –
7.14 (m, 1H), 7.11 – 7.05 (m, 2H), 6.65 (d, J = 47.9 Hz, 1H),
4.38 – 4.23 (m, 3H), 4.02 (dd, J = 14.6, 4.1 Hz, 1H), 3.91
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900820
Advanced Synthesis & Catalysis
(dq, J = 14.4, 3.0 Hz, 1H), 3.85 – 3.81 (m, 1H), 3.76 – 3.68
(m, 1H), 2.07 – 2.01 (m, 1H), 1.92 – 1.82 (m, 2H), 1.76 –
1.71 (m, 1H), 1.26 (t, 6.9 Hz, 3H). 13C NMR (151 MHz,
CDCl3) δ 164.65 (d, JC-F = 35.8 Hz, 1C), 153.36, 130.22,
126.23 (d, JC-F = 2.9 Hz, 1C), 123.11, 122.03, 109.61,
109.24, 85.10 (d, JC-F = 212.2 Hz, 1C), 68.28, 62.97, 45.69,
28.95, 28.89, 25.65, 13.98. IR (KBr, cm-1): 3066, 2957,
2927, 2871, 2857, 1767, 1724, 1618, 1493, 1401, 1376,
= 5.4 Hz, 2H), 4.42 – 4.29 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H).
13C NMR (151 MHz, CDCl3) δ 164.66 (d, JC-F = 35.9 Hz,
1C), 152.83, 136.00, 133.54, 129.55, 128.63, 128.09,
126.56, 126.38 (d, JC-F = 2.7 Hz, 1C), 123.20, 122.67,
122.17, 109.54, 108.97, 85.20 (d, JC-F = 212.6 Hz, 1C),
63.04, 43.47, 14.03. IR (KBr, cm-1): 3062, 3027, 2982, 2926,
1766, 1725, 1617, 1492, 1399, 1375, 1227, 1050, 1014, 755,
+
692. HRMS (ESI) for C20H20FN2O3 (M+H)+: calcd
+
1227, 1059, 1013, 756. HRMS (ESI) for C16H20FN2O4
355.14525, found 355.14560.
(M+H)+: calcd 323.14016, found 323.14078.
Ethyl
2-(3-benzyl-2-oxo-2,3-dihydro-1H-
Ethyl
2-(3-(2-cyanoethyl)-2-oxo-2,3-dihydro-1H-
benzo[d]imidazol-1-yl)-2-fluoroacetate (21). Yellow solid.
benzo[d]imidazol-1-yl)-2-fluoroacetate (16). Yellow solid. M.P.: 72.6 – 73.9 C. 77% Yield (51 mg, Eluent:
1
M.P.: 101.2 – 102.9 C. 58% Yield (34 mg, Eluent:
EtOAc/petroleum = 1:6). H NMR (600 MHz, CDCl3) δ
7.33 (d, J = 4.4 Hz, 4H), 7.28 (dd, J = 8.8, 4.4 Hz, 1H), 7.14
– 7.10 (m, 1H), 7.10 – 7.04 (m, 2H), 6.93 – 6.88 (m, 1H),
6.72 (d, J = 47.8 Hz, 1H), 5.10 (d, J = 15.7 Hz, 1H), 5.06 (d,
J = 15.8 Hz, 1H), 4.40 – 4.29 (m, 2H), 1.27 (t, J = 7.1 Hz,
3H). 13C NMR (151 MHz, CDCl3) δ 164.63 (d, JC-F = 35.9
Hz, 1C), 153.24, 135.49, 129.46, 128.88, 127.96, 127.45,
126.40 (d, JC-F = 2.9 Hz, 1C), 123.16, 122.21, 109.54,
109.00, 85.27 (d, JC-F = 212.5 Hz, 1C), 63.03, 45.16, 14.00.
IR (KBr, cm-1): 3064, 3031, 2956, 2923, 2853, 1764, 1716,
1613, 1490, 1455, 1397, 1375, 1225, 1044, 1011, 751, 695.
1
EtOAc/petroleum = 1:2). H NMR (600 MHz, CDCl3) δ
7.23 – 7.18 (m, 1H), 7.16 – 7.10 (m, 3H), 6.63 (d, J = 47.7
Hz, 1H), 4.39 – 4.27 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 2.85
(td, J = 6.9, 1.7 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR
(151 MHz, CDCl3) δ 164.30 (d, JC-F = 35.4 Hz, 1C), 152.61,
128.62, 126.31 (d, JC-F = 2.8 Hz, 1C), 123.52, 122.81,
116.93, 109.94, 108.15, 85.01 (d, JC-F = 213.3 Hz, 1C),
63.15, 37.48, 17.06, 13.96. IR (KBr, cm-1): 3068, 2982,
2967, 2941, 2252, 1766, 1728, 1615, 1493, 1401, 1376,
+
1229, 1057, 1024, 755. HRMS (ESI) for C14H15FN3O3
(M+H)+: calcd 292.10920, found 292.10956.
HRMS (ESI) for C18H18FN2O3 (M+H)+: calcd 329.12960,
+
found 329.12985.
Ethyl
2-(3-(but-3-enyl)-2-oxo-2,3-dihydro-1H-
benzo[d]imidazol-1-yl)-2-fluoroacetate (17). Yellow oil.
Ethyl 2-fluoro-2-(2-oxo-3-((perfluorophenyl)methyl)-
1
77% Yield (45 mg, Eluent: EtOAc/petroleum = 1:6). H
2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetate
(22).
NMR (600 MHz, CDCl3) δ 7.16 (t, J = 7.5 Hz, 1H), 7.11 –
7.07 (m, 2H), 7.03 (d, J = 7.8 Hz, 1H), 6.65 (d, J = 47.9 Hz,
1H), 5.86 – 5.77 (m, 1H), 5.11 – 5.01 (m, 2H), 4.39 – 4.24
(m, 2H), 3.95 (t, J = 7.3 Hz, 2H), 2.52 (q, J = 7.0 Hz, 2H),
1.25 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ
164.65 (d, JC-F = 36.0 Hz, 1C), 152.92, 133.98, 129.56,
126.31 (d, JC-F = 3.0 Hz, 1C), 123.03, 121.95, 117.84,
109.51, 108.38, 85.09 (d, JC-F = 212.2 Hz, 1C), 62.95, 40.88,
32.36, 13.97. IR (KBr, cm-1): 3069, 2979, 2958, 2925, 2853,
1767, 1723, 1641, 1618, 1493, 1400, 1375, 1225, 1055,
Yellow oil. 86% Yield (72 mg, Eluent: EtOAc/petroleum =
1
1:6). H NMR (600 MHz, CDCl3) δ 7.19 – 7.07 (m, 3H),
7.01 (d, J = 7.7 Hz, 1H), 6.64 (d, J = 47.6 Hz, 1H), 5.18 (s,
2H), 4.38 – 4.26 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR
(151 MHz, CDCl3) δ 164.37 (d, JC-F = 35.7 Hz, 1C), 152.47,
145.69 (dm, JC-F = 249.3 Hz; 146.52 – 146.32, 144.86 –
144.63, 1C), 141.62 (dm, JC-F = 246.5 Hz; 142.44 – 142.21,
140.80 – 140.52, 1C), 137.81 (dm, JC-F = 256.8 Hz; 138.66
– 138.35, 136.96 – 136.66, 1C), 128.54, 126.38 (d, JC-F
=
2.7 Hz, 1C), 123.39, 122.68, 109.79, 108.79 (td, JC-F = 18.0,
2.5 Hz, 1C), 108.14, 85.12 (d, JC-F = 212.9 Hz, 1C), 63.09,
33.10, 13.88. IR (KBr, cm-1): 3068, 2986, 2968, 2946, 1766,
1735, 1657, 1616, 1523, 1508, 1493, 1401, 1367, 1230,
1127, 1050, 1022, 754, 689. HRMS (ESI) for
C18H13F6N2O3+ (M+H)+: calcd 419.08249, found 419.08292.
1023, 754. HRMS (ESI) for C15H18FN2O3 (M+H)+: calcd
+
293.12960, found 293.12988.
Ethyl
2-(3-allyl-2-oxo-2,3-dihydro-1H-
benzo[d]imidazol-1-yl)-2-fluoroacetate (18). Yellow oil.
1
90% Yield (50 mg, Eluent: EtOAc/petroleum = 1:6). H
NMR (600 MHz, CDCl3) δ 7.14 – 7.09 (m, 2H), 7.09 – 7.04
(m, 1H), 6.99 (d, J = 7.7 Hz, 1H), 6.66 (d, J = 47.9 Hz, 1H),
5.91 – 5.85 (m, 1H), 5.24 – 5.20 (m, 2H), 4.49 (d, J = 5.2
Hz, 2H), 4.37 – 4.24 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H). 13C
NMR (151 MHz, CDCl3) δ 164.58 (d, JC-F = 35.8 Hz, 1C),
152.72, 131.25, 129.46, 126.28 (d, JC-F = 2.9 Hz, 1C),
Ethyl
2-(6-bromo-3-methyl-2-oxo-2,3-dihydro-1H-
imidazo[4,5-b]pyridin-1-yl)-2-fluoroacetate (23). White
solid. M.P.: 135.4 – 136.2 C. 56% Yield (37 mg, Eluent:
1
EtOAc/petroleum = 1:5). H NMR (600 MHz, CDCl3) δ
8.18 (d, J = 1.7 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 6.66 (d, J
= 47.1 Hz, 1H), 4.48 – 4.20 (m, 2H), 3.48 (s, 3H), 1.31 (t, J
= 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 163.86 (d, JC-
123.09, 122.07, 117.94, 109.37, 108.92, 85.14 (d, JC-F
=
212.3 Hz, 1C), 62.97, 43.64, 13.94. IR (KBr, cm-1): 3068,
2983, 2925, 2854, 1765, 1724, 1646, 1618, 1491, 1396,
1375, 1224, 1048, 1016, 754. HRMS (ESI) for
C14H16FN2O3+ (M+H)+: calcd 279.11395, found 279.11411.
F = 35.4 Hz, 1C), 152.30, 143.08, 142.72, 121.44 (d, JC-F =
2.8 Hz, 1C), 118.99, 112.89, 84.73 (d, JC-F = 214.1 Hz, 1C),
63.43, 26.36, 14.00. IR (KBr, cm-1): 2978, 2923, 2854, 1748,
1613, 1594, 1489, 1415, 1393, 1259, 1220, 1059, 1016, 875,
746, 584. HRMS (ESI) for C11H12FBrN3O3+ (M+H)+: calcd
332.00406, found 332.00461.
Ethyl 2-fluoro-2-(3-(2-methylallyl)-2-oxo-2,3-dihydro-
1H-benzo[d]imidazol-1-yl)acetate (19). Yellow oil. 82%
1
Yield (48 mg, Eluent: EtOAc/petroleum = 1:5). H NMR
Ethyl
2-fluoro-2-(2-oxo-3-phenyl-2,3-dihydro-1H-
(600 MHz, CDCl3) δ 7.14 – 7.07 (m, 3H), 7.00 (d, J = 7.7
Hz, 1H), 6.67 (d, J = 47.8 Hz, 1H), 4.96 (s, 1H), 4.86 (s, 1H),
4.44 (s, 2H), 4.37 – 4.26 (m, 2H), 1.74 (s, 3H), 1.24 (t, J =
7.2 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 164.61 (d, JC-F
imidazol-1-yl)acetate (24). Brown oil. 68% Yield (36 mg,
1
Eluent: EtOAc/petroleum = 1:4). H NMR (600 MHz,
CDCl3) δ 7.56 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H),
7.27 (t, J = 7.2 Hz, 1H), 6.66 (d, J = 1.9 Hz, 1H), 6.59 (d, J
= 2.9 Hz, 1H), 6.47 (d, J = 49.2 Hz, 1H), 4.40 – 4.31 (m,
2H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3)
= 36.0 Hz, 1C), 153.04, 138.96, 129.65, 126.27 (d, JC-F
=
3.0 Hz, 1C), 123.09, 122.10, 113.10, 109.42, 109.06, 85.24
(d, JC-F = 212.2 Hz, 1C), 62.96, 47.23, 19.74, 13.96. IR (KBr, δ 164.45 (d, JC-F = 35.1 Hz, 1C), 151.11, 136.43, 129.31,
cm-1): 3068, 2980, 2924, 2854, 1766, 1722, 1660, 1615,
1492, 1396, 1376, 1225, 1051, 1023, 753. HRMS (ESI) for
C15H18FN2O3+ (M+H)+: calcd 293.12960, found 293.12982.
126.46, 121.79, 112.40, 108.62, 85.49 (d, JC-F = 212.1 Hz,
1C), 62.95, 13.98. IR (KBr, cm-1): 3065, 2981, 2926, 2854,
1738, 1694, 1598, 1502, 1458, 1409, 1206, 1096, 1024, 758,
+
694. HRMS (ESI) for C13H14FN2O3 (M+H)+: calcd
265.09830, found 265.09854.
(E)-ethyl
2-fluoro-2-(2-oxo-3-(3-phenylallyl)-2,3-
dihydro-1H-benzo[d]imidazol-1-yl)acetate (20). Yellow
oil. 93% Yield (66 mg, Eluent: EtOAc/petroleum = 1:6). 1H
NMR (600 MHz, CDCl3) δ 7.36 (d, J = 7.8 Hz, 2H), 7.30 (t,
J = 7.3 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 7.15 (t, J = 6.8 Hz,
2H), 7.12 – 7.08 (m, 2H), 6.72 (d, J = 47.9 Hz, 1H), 6.65 (d,
J = 15.9 Hz, 1H), 6.27 (dt, J = 15.8, 6.0 Hz, 1H), 4.69 (d, J
Ethyl 2-(3-(4-acetyl-2-fluorophenyl)-2-oxo-2,3-dihydro-
1H-imidazol-1-yl)-2-fluoroacetate (25). Yellow solid.
M.P.: 39.9 – 41.4 C. 41% Yield (27 mg, Eluent:
1
EtOAc/petroleum = 1:3). H NMR (600 MHz, CDCl3) δ
7.88 – 7.84 (m, 1H), 7.80 – 7.60 (m, 2H), 6.67 (t, J = 2.8 Hz,
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900820
Advanced Synthesis & Catalysis
1H), 6.61 (d, J = 3.3 Hz, 1H), 6.43 (d, J = 49.0 Hz, 1H), 4.40
– 4.30 (m, 2H), 2.59 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). 13C
NMR (151 MHz, CDCl3) δ 195.62, 164.19 (d, JC-F = 34.7
Hz, 1C), 155.19 (d, JC-F = 252.8 Hz, 1C), 151.04, 137.11 (d,
JC-F = 5.8 Hz, 1C), 127.92 (d, JC-F = 11.0 Hz, 1C), 126.45,
124.84 (d, JC-F = 3.3 Hz, 1C), 116.42 (d, JC-F = 21.1 Hz, 1C),
113.51 (d, JC-F = 5.4 Hz, 1C), 108.89, 85.47 (d, JC-F = 212.9
Hz, 1C), 63.08, 26.54, 13.98. IR (KBr, cm-1): 3072, 2985,
2925, 1763, 1716, 1687, 1614, 1577, 1425, 1369, 1271,
C. Debitus, O. Ribes, J. Pusset, S. Leroy, F. Pietra. J.
Chem. Soc., Chem. Commun. 1993, 1305-1306. e) P. B.
Koswatta, C. Lovely. J. Nat. Prod. Rep. 2011, 28, 511-
528.
[2] R. W. Carling, K. W. Moore, C. R. Moyes, E. A. Jones,
K. Bonner, F. Emms, R. Marwood, S. Patel, S. Patel, A.
E. Fletcher, M. Beer, B. Sohal, A. Pike, P. D. Leeson.J.
Med. Chem. 1999, 42, 2706-2715.
+
1233, 1198, 743, 658. HRMS (ESI) for C15H15F2N2O4
(M+H)+: calcd 325.09944, found 325.09982.
[3] J. J. Bronson, K. L. DenBleyker, P. L. Falk, R. A. Mate,
H.-T. Ho, M. J. Pucci, L. B. Snyder.Bioorg. Med. Chem.
Lett. 2003, 13, 873-875.
Ethyl
2-(3-methyl-2-oxo-2,3-dihydro-1H-
benzo[d]imidazol-1-yl)acetate (26). CAS number:
1153349-40-6. White solid. M.P.: 105.6 – 107.1 C. 68%
1
Yield (32 mg, Eluent: EtOAc/petroleum = 1:4). H NMR
[4] a) C. Congiu, M. T. Cocco, V. Onnis. Bioorg. Med.
Chem. Lett. 2008, 18, 989-993. b) N. Xue, X. Yang, R.
Wu, J. Chen, Q. He, B. Yang, X. Lu, Y. Hu. Bioorg. Med.
Chem. 2008, 16, 2550-2557.
(600 MHz, CDCl3) δ 7.13 – 7.06 (m, 2H), 6.99 (d, J = 8.0
Hz, 1H), 6.88 (d, J = 7.3 Hz, 1H), 4.62 (s, 2H), 4.22 (q, J =
7.1 Hz, 2H), 3.43 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR
(151 MHz, CDCl3) δ 167.84, 154.28, 130.14, 129.07,
121.75, 121.46, 107.68, 107.55, 61.74, 42.35, 27.25, 14.13.
IR (KBr, cm-1): 3062, 2924, 2853, 1709, 1621, 1500, 1439,
1401, 1376, 1206, 1052, 1011, 754.
[5] K. Watanabe, Y. Morinaka, Y. Hayashi, M. Shinoda, H.
Nishi, N. Fukushima, T. Watanabe, A. Ishibashi, S. Yuki,
M. Tanaka. Bioorg. Med. Chem. Lett. 2008, 18, 1478-
1483.
Ethyl
2-(3,5,6-trimethyl-2-oxo-2,3-dihydro-1H-
benzo[d]imidazol-1-yl)acetate (27). CAS number:
2114881-86-4. White solid. M.P.: 145.6 – 146.2 C. 34%
1
Yield (19 mg, Eluent: EtOAc/petroleum = 1:5). H NMR
[6] S. Nakamura, N. Tsuno, M. Yamashita, I. Kawasaki, S.
Ohta, Y. Ohishi. J. Chem. Soc. Perkin Trans. 1, 2001,
429-436.
(600 MHz, CDCl3) δ 6.76 (s, 1H), 6.66 (s, 1H), 4.57 (s, 2H),
4.22 (q, J = 7.1 Hz, 2H), 3.38 (s, 3H), 2.29 (s, 3H), 2.27 (s,
3H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3)
δ 168.03, 154.39, 129.85, 129.53, 128.24, 127.17, 108.92,
108.74, 61.63, 42.36, 27.19, 19.91, 14.13. IR (KBr, cm-1):
2961, 2918, 2852, 1744, 1713, 1696, 1508, 1446, 1417,
1374, 1216, 1023, 885, 745, 650.
[7] R. Das, M. Banerjee, R. K. Rai, R. Karri, G. Roy. Org.
Biomol. Chem. 2018, 16, 4243-4260.
[8] I. M. AlNashef, M. A. Hashim, F. S. Mjalli, M. Q. Al-
haj Ali, M. Hayyan. Tetrahedron Lett. 2010, 51, 1976-
1978.
Ethyl
2-(6-bromo-3-methyl-2-oxo-2,3-dihydro-1H-
imidazo[4,5-b]pyridin-1-yl)acetate (28).[19] White solid.
M.P.: 154.1 – 156.0 C. 54% Yield (34 mg, Eluent:
1
EtOAc/petroleum = 1:5). H NMR (600 MHz, CDCl3) δ
[9] a) H. M. Lima, C. J. Lovely. Org. Lett. 2011, 13, 5736-
5739. b) D. Li, T. Ollevier. Org. Lett. 2019, 21, 3572-
3575.
8.08 (d, J = 1.6 Hz, 1H), 7.21 (d, J = 1.7 Hz, 1H), 4.57 (s,
2H), 4.22 (q, J = 7.1 Hz, 2H), 3.45 (s, 3H), 1.27 (t, J = 7.1
Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 167.08, 153.51,
142.66, 141.49, 124.52, 116.49, 112.36, 62.13, 42.02, 26.19,
14.09. IR (KBr, cm-1): 3062, 2981, 2924, 2852, 1705, 1614,
1590, 1493, 1436, 1396, 1375, 1256, 1220, 1160, 885, 754,
636.
[10] J.-P. Li, Y. Huang, M.-S. Xie, G.-R. Qu, H.-Y. Niu, H.-
X. Wang, B.-W. Qin, H.-M. Guo. J. Org. Chem. 2013,
78, 12629-12636.
[11] V. A. Peshkov, O. P. Pereshivko, S. Sharma, T.
Meganathan, V. S. Parmar, D. S. Ermolat’ev, E. V.
Van der Eycken. J. Org. Chem. 2011, 76, 5867-5872.
1-benzyl-3-methyl-1H-benzo[d]imidazol-2(3H)-one
(29).[9a] Yellow solid. M.P.: 87.0 – 89.0 C. 31% Yield (15
1
mg, Eluent: EtOAc/petroleum = 1:4). H NMR (600 MHz,
CDCl3) δ 7.35 – 7.28 (m, 4H), 7.27 – 7.25 (m, 1H), 7.08 (td,
J = 7.7, 1.0 Hz, 1H), 7.02 – 7.98 (m, 2H), 6.88 (d, J = 7.7
Hz, 1H), 5.08 (s, 2H), 3.47 (s, 3H). 13C NMR (151 MHz,
CDCl3) δ 154.60, 136.38, 130.13, 129.20, 128.72, 127.65,
127.48, 121.32, 121.25, 108.20, 107.43, 44.91, 27.24. IR
(KBr, cm-1): 3060, 3031, 2955, 2924, 2854, 1703, 1620,
1610, 1497, 1456, 1439, 1400, 1389, 1357, 1249, 1173, 748,
698.
[12] H. Zhang, D. Huang, K.-H. Wang, J. Li, Y. Su, Y. Hu.
J. Org. Chem. 2017, 82, 1600-1609.
[13] a) J.-C. Deng, Y.-C. Gao, Z. Zhu, Li. Xu, Z.-D. Li, R.-
Y. Tang. Org. Lett. 2019, 21, 545-548. b) J.-C. Deng,
J.-H. Chen, J.-R. Zhang, T.-T. Lu, R.-Y. Tang. Adv.
Synth. Catal. 2018, 360, 4795-4806.
Acknowledgements
[14] a) P. Kirsch. Modern Fluoroorganic Chemistry:
Synthesis, Reactivity, Applications. Wiley-VCH,
Weinheim, 2013. b) J. P. Bꢀguꢀ, D. Bonnet-Delpon.
Bioorganic and Medicinal Chemistry of Fluorine.
Wiley, Hoboken, NJ, 2008. c) Y. Zhou, J. Wang, Z. Gu,
S. Wang, W. Zhu, J. L. Acena, V. A. Soloshonok, K.
Izawa, H. Liu. Chem. Rev. 2016, 116, 422-518. d) J.
Wang, M. Sanchez-Rosello, J. L. Acena, C. del Pozo,
A. E. Sorochinsky, S. Fustero, V. A. Soloshonok, H.
Liu. Chem. Rev. 2014, 114, 2432-2506. e) E. P. Gillis,
K. J. Eastman, M. D. Hill, D. J. Donnelly, N. A.
Meanwell. J. Med. Chem. 2015, 58, 8315-8359.
We gratefully thank the South China Agricultural University, and
Science Technology Program Project of Guangdong Province (No.
2016B020204005) for their financial support.
References
[1] a) R. Akee, T. R. Carroll, W. Y. Yoshida, P. J. Scheuer,
T. J. Stout, J. Clardy. J. Org. Chem. 1990, 55, 1944-1946.
b) X. Fu, J. R. Barnes, T. Do, F. J. Schmitz. J. Nat. Prod.
1997, 60, 497-498. c) P. Ralifo, P. Crews. J. Org. Chem.
2004, 69, 9025-9029. d) M. D’Ambrosio, A. Guerriero,
7
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10.1002/adsc.201900820
Advanced Synthesis & Catalysis
[15] X.-D. Tang, W.-Q. Wu, W. Zeng, H.-F. Jiang. Acc.
Chem. Res. 2018, 51, 1092-1105.
[16] a) D. J. Dumas. U.S. Patent 1999/5990315 A, 1999. b)
K. M. Poss. PCT Int. Pat. WO 1990/9002120 A1, 1990.
c) N. Sato, M. Ando, S. Ishikawa, T. Nagase, K. Nagai,
A. Kanatani. U.S. Patent 20040072874 A1, 2004.
[17] a) W. Fu, Q. Song, Org. Lett. 2018, 20, 393-396. b) X.-
H. Ouyang, R.-J. Song, J.-H. Li, Chem. Asian J. 2018,
13, 2316-2332.
[18] References for radical addition with alkoxyamine, see:
a) C. Wetter, K. Jantos, K. Woithe, A. Studer. Org. Lett.
2003, 5, 2899-2902. b) C. Wetter, A. Studer. Chem.
Commun. 2004, 174-175. c) A. Teichert, K. Jantos, K.
Harms, A. Studer. Org. Lett. 2004, 6, 3477-3480. d) I. C.
Wienhoefer, A. Studer, M. T. Rahman, T. Fukuyama, I.
Ryu. Org. Lett. 2009, 11, 2457-2460. e) Q.-L. Zhu, E. C.
Gentry, R. R. Knowles. Angew. Chem. Int. Ed. 2016, 55,
9969-9973. f) E. C. Gentry, L. J. Rono, M. E. Hale, R.
Matsuura, R. R. Knowles. J. Am. Chem. Soc. 2018, 140,
3394-3402.
[19] C. C. Chrovian, M. A. Letavic, J. C. Rech, D. A.
Rudolph, A. S. Johnson, B. M. Stenne, J. L. Wall. PCT
Int. Appl. WO 2018067786 A1, 2018.
8
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10.1002/adsc.201900820
Advanced Synthesis & Catalysis
UPDATE
TEMPO-Mediated Synthesis of N-(Fluoroalkyl)
imidazolones via the Reaction of Imidazoles with
Iodofluoroacetate
Adv. Synth. Catal. Year, Volume, Page – Page
Jia-Hao Chen,a Ahmed Wasim,a Ming-Hua Li,a
Zhao-Dong Li,a Zi-Ning Cui*a and Ri-Yuan Tang*ab
9
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